MYO7A mutation screening in Usher syndrome type I patients from diverse origins
MYO7A mutation screening in Usher syndrome type I patients from diverse origins
复制标题
DOI：
10.1136/jmg.2006.045377
复制
发表时间：
2007-03-01
影响因子：
4
通讯作者：
Millan, J. M.
中科院分区：
文献类型：
--
作者：
Jaijo, T.;Aller, E.;Millan, J. M.
从表型上看，根据听力损害的严重程度、视网膜色素变性发作的年龄和前庭反应的存在或不存在，已经定义了三种临床类型的Usher综合征。Usher综合征I型（USH 1）是最严重的类型，其特征是严重至极严重的先天性感音神经性听力损失、平衡缺陷和青春期前视网膜色素变性发作，导致失明。USH 2的特征是中度至重度听力障碍，前庭功能正常，视网膜变性的发病时间比USH 1晚。USH 3表现为进行性听力损失、视网膜色素变性和可变的前庭表型。USH 1的6个位点（USH 1B-USH 1G）已被定位，迄今已鉴定出5个基因。MYO 7A基因被发现与USH 1B 6有关，是USH 1最常见的亚型，约占病例的50%。7-9 MYO 7A缺陷还导致常染色体显性非综合征性感觉神经性听力损伤（DFNA 11）（MIM 601317）、10常染色体隐性耳聋（DFNB 2）（MIM 600060）11 12以及临床上类似于USH 3的非典型类型的Usher综合征。MYO 7A基因具有49个外显子，其中48个是编码的，并且跨越染色体11 q13上的约87 kb的基因组序列。5.编码的蛋白质是一种非常规的肌球蛋白，肌球蛋白VIIA，14预测由2215个氨基酸组成，分子量为254 kDa。这种蛋白质包含三个典型的结构域：N末端头部或马达;由五个IQ基序组成的颈部或调节结构域;以及以短卷曲螺旋结构域开始的尾部，随后是两个大的重复序列，每个重复序列包含MyTH 4和FERM结构域，由SH 3结构域分开。在人类中，肌球蛋白VIIA在多种组织中表达：内耳、视网膜、睾丸、肺和肾。16肌球蛋白VIIA在内耳中的不同作用已经被假定，例如参与毛细胞中的信号转导以及毛细胞静纤毛的分化和组织。在人视网膜中，肌球蛋白VIIA在RPE黑素体的迁移、光感受器细胞外节尖端的吞噬作用和通过这些光感受器的纤毛的视蛋白运输中显示出活跃的功能。18 19
Phenotypically, three clinical types of Usher syndrome have been defined according to the severity of hearing impairment, age of retinitis pigmentosa onset and the presence or absence of vestibular response. Usher syndrome type I (USH1) is the most serious type, characterised by severe to profound congenital sensorineural hearing loss, balance deficiency and prepubertal onset of retinitis pigmentosa leading to blindness. USH2 is characterised by moderate to severe hearing impairment, normal vestibular function and later onset of retinal degeneration than USH1. USH3 displays progressive hearing loss, retinitis pigmentosa and variable vestibular phenotype.Six loci for USH1 (USH1B–USH1G) have been mapped and, to date, five genes have been identified. 4 5 The MYO7A gene was found to be responsible for USH1B6 and is the most common subtype of USH1, accounting for approximately 50% of cases. 7–9 Defects in MYO7A also cause autosomal dominant nonsyndromic sensorineural hearing impairment (DFNA11)(MIM 601317), 10 autosomal recessive deafness (DFNB2)(MIM 600060) 11 12 as well as atypical types of Usher syndrome which are clinically similar to USH3. 13 The MYO7A gene has 49 exons, of which 48 are coding, and spans approximately 87 kb of genomic sequence on chromosome 11q13. 5. The encoded protein is an unconventional myosin, the myosin VIIA, 14 predicted to consist of 2215 amino acids and has a molecular mass of 254 kDa. This protein contains three typical domains: the N terminal head or motor; the neck or regulatory domain consisting of five IQ motifs; and the tail which begins with a short coiled coil domain followed by two large repeats, each containing a MyTH4 and a FERM domain, separated by a SH3 domain. 15 In humans, myosin VIIA is expressed in a variety of tissues: the inner ear, retina, testis, lung and kidney. 16 Different roles have been postulated for myosin VIIA in the inner ear, such as participation in signal transduction in hair cells and differentiation and organisation of hair cell stereocilia. 17 In the human retina, myosin VIIA displays an active function in the migration of RPE melanosomes, phagocytosis of photoreceptor cell outer segment tips and opsin transport through the cilium of these photoreceptors. 18 19